title: Detrimental effects of albuterol on airway responsiveness requires airway inflammation and is independent of β-receptor affinity in murine models of asthma.
abstract: BACKGROUND
  Inhaled short acting β2-agonists (SABA), e.g. albuterol, are used for quick reversal of bronchoconstriction in asthmatics. While SABA are not recommended for maintenance therapy, it is not uncommon to find patients who frequently use SABA over a long period of time and there is a suspicion that long term exposure to SABA could be detrimental to lung function. To test this hypothesis we studied the effect of long-term inhaled albuterol stereoisomers on immediate allergic response (IAR) and airway hyperresponsiveness (AHR) in mouse models of asthma.
  
  
  METHODS
  Balb/C mice were sensitized and challenged with ovalbumin (OVA) and then we studied the IAR to inhaled allergen and the AHR to inhaled methacholine. The mice were pretreated with nebulizations of either racemic (RS)-albuterol or the single isomers (S)- and (R)-albuterol twice daily over 7 days prior to harvest.
  
  
  RESULTS
  We found that all forms of albuterol produced a significant increase of IAR measured as respiratory elastance. Similarly, we found that AHR was elevated by albuterol. At the same time a mouse strain that is intrinsically hyperresponsive (A/J mouse) was not affected by the albuterol isomers nor was AHR induced by epithelial disruption with Poly-L-lysine affected by albuterol.
  
  
  CONCLUSIONS
  We conclude that long term inhalation treatment with either isomer of albuterol is capable of precipitating IAR and AHR in allergically inflamed airways but not in intrinsically hyperresponsive mice or immunologically naïve mice. Because (S)-albuterol, which lacks affinity for the β2-receptor, did not differ from (R)-albuterol, we speculate that isomer-independent properties of the albuterol molecule, other than β2-agonism, are responsible for the effect on AHR.
authors.affiliation: Vermont Lung Center, Department of Medicine, University of Vermont, 149 Beaumont Ave, Burlington, VT 05401, USA. lennart.lundblad@uvm.edu
authors.forename: Lennart K A
authors.initials: LK
authors.lastname: Lundblad
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rinaldi
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.forename: Erik P
authors.initials: EP
authors.lastname: Riesenfeld
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Steven
authors.initials: S
authors.lastname: Aimi
authors.forename: Leesa M
authors.initials: LM
authors.lastname: Barone
authors.forename: Jason H T
authors.initials: JH
authors.lastname: Bates
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry; D000420:Albuterol / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry; D000704:Analysis of Variance; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D007536:Isomerism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009330:Nebulizers and Vaporizers; D010047:Ovalbumin; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D015656:Respiratory Mechanics / Q000187:drug effects; D013997:Time Factors
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D011943:Receptors, Adrenergic, beta; D010047:Ovalbumin; D000420:Albuterol